DE69932154T2 - USE OF N-SUBSTITUIRTE 1,5-DIDEOXY-1,5-IMINO-D-GLUCITOLS FOR THE TREATMENT OF HEPATITIS INFECTIONS - Google Patents

Abstract

Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immuno-stimulating agents.

Description

DATA RELATED REGISTRATIONS

These The application claims the priority of the US application with the preliminary Registration Serial Number 60/074 508, filed February 12, 1998. This application is also a divisional application of the U.S. application Serial No. 09 / 023,401, filed February 12, 1998. The contents of each of these applications are incorporated herein by reference included in their entirety.

BACKGROUND THE INVENTION

Territory of invention

The The present invention relates to methods and compositions for Treatment of hepatitis virus infections, especially hepatitis B virus infections in mammals, especially in humans. The methods include (1) administration N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleosides as antiviral agents, Nucleotides as antiviral agents, mixtures thereof or immunomodulating / immunostimulating Or (2) the administration of N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination with nucleosides as antiviral agents, Nucleotides as antiviral agents or mixtures thereof and immunomodulating / immunostimulating Medium. Such combinations of antiviral agents for hepatitis show unexpected efficacy in replication inhibition and the distribution of hepatitis viruses in mammalian cells infected with these viruses.

description of the prior art

Hepatitis viruses

The Hepatitis B virus (HBV, HepB) is the causative agent of acute and chronic liver disease including liver fibrosis, cirrhosis, inflammatory Liver disease and liver cancer, which in some patients to Lead death can (Joklik, Wolfgang K., Virology, 3rd Edition, Appleton & Lange, Norwalk, Connecticut, 1988 (ISBN 0-8385-9462-X)). Although effective vaccines are available, are still more than 300 million people worldwide, i. 5% the world population, chronically infected with the virus (Locarnini, S.A. et al., Antiviral Chemistry & Chemotherapy, 1996, 7 (2), 53-64). Such vaccines have no therapeutic value for already persons infected with the virus. In Europe and North America are between 0.1% and 1% of the population infected. By estimates 15% to 20% of people who contract the infection develop Cirrhosis or other chronic obstruction by the HBV infection. Once the cirrhosis of the liver is established has, come in considerable Measurements of morbidity and mortality with one about 5 years of survival of the patients (Blume, H.E. et al., Advanced Drug Delivery Reviews, 1995, 17, 321-331). It is therefore necessary and of high priority, improved and effective anti-HBV anti-hepatitis therapies (Locarnini, S.A. et al., Antiviral Chemistry & Chemotherapy, 1996, 7 (2), 53-64).

Further, as cause of human diseases significant hepatitis viruses include hepatitis A, hepatitis B, hepatitis C, hepatitis delta, Hepatitis E, Hepatitis F and Hepatitis G (Coates, J.A.V. et al. Exp. Opin. Ther. Patents, 1995, 5 (8), 747-756). There are also animal hepatitis viruses, which are species specific. These include, for example, those the ducks, woodchucks and mice infect.

1,5-dideoxy-1,5-imino-D-glucitol compounds

1,5-dideoxy-1,5-imino-D-glucitol (also known as 1-deoxynojirimycin, DNJ) and its N-alkyl derivatives (collectively referred to as "iminosugars") are known inhibitors the N-linked oligosaccharide-processing enzyme α-glucosidase I and II (Saunier et al., J. Biol. Chem., 1982, 257, 14155-14161; Elbein, Ann. Rev. Biochem., 1987, 56, 497-534). As glucose analogues they also have potential to inhibit glucose transport, glucosyltransferases and / or glycolipid synthesis (Newbrun et al., Arch. Oral Biol., 1983, 28, 516-536, Wang et al., Tetrahedron Lett., 1993, 34, 403-406). Your inhibition activity against glucosidases has led to the further development of these components as antihyperglycemic and antiviral agents. See, for example, PCT International Publication WO 87/03903 and US Pat U.S. Patents 4,065,562, 4,182,767, 4,533,668, 4,639,436, 4,849 430, 4,957,926, 5,011,829 and 5,030,638.

For glucosidase inhibitors such as N-alkyl-1,5-dideoxy-1,5-imino-D-glucitol compounds, wherein the alkyl group contains between 3 and 6 carbon atoms has been shown to be effective in the treatment of hepatitis B infection (International PCT Publication WO 95/19172). For example, N- (n-butyl) -deoxynojirimycin (N-butyl-DNJ, N- (n-butyl) -1,5-dideoxy-1,5-imino-D-glucitol) is effective for this purpose (Block, TM, Proc Natl Acad Sci USA, 1994, 91, 2235-2239, Ganem, B., Chemtracts: Organic Chemistry, 1994, 7 (2), 106-107). N-butyl-DNJ has also been tested as an anti-HIV-1 agent in HIV-infected patients and is known to be well tolerated. Another α-glucosidase inhibitor, deoxynojirimycin (DNJ), has also been proposed as an antiviral agent for use in combination with N- (phosphonoacetyl) -L-aspartic acid (PALA) (WO 93/18763). However, combinations of N-substituted-imino-D-glucitol derivatives and other antiviral agents for the treatment of hepatitis virus infections have not previously been disclosed or suggested. From the results obtained in the woodchuck model of hepatitis viral infection, Block et al., 1998, Nature Medicine 4 (5), 610-614, have suggested that glucosidase inhibitors such as N-nonyl-DNJ, which are produced by specific steps of the N- linked glycosylation pathway of the hepatitis virus glycoproteins, useful for the targeted disruption of the Glycosilierungsablaufs as a therapeutic intervention in hepatitis B virus.

nucleosides and nucleotides as antiviral agents

Reverse transcriptase inhibitors, including the class of nucleoside and nucleotide analogs, were first developed as drugs for the treatment of retroviruses such as human immunodeficiency virus (HIV), the causative agent of AIDS. Increasingly, these compounds have found utility against other viruses, including both RNA and DNA viruses, through viral screening and chemical modification techniques. Nucleoside and nucleotide analogs exert their antiviral activity by inhibiting the corresponding DNA and RNA polymerases responsible for the synthesis of the viral DNA or RNA. Because viruses contain different forms of polymerases, the same nucleoside / nucleotide compound can affect different viruses in dramatically different ways. For example, lamivudine (3TC ^®) appears to be useful against HBV infection, whereas zidovudine (AZT ^®) seems to have little use against the same virus (Gish, RG et al., Exp. Opin. Invest. Drugs, 1995, 4 (2), 95-115).

The toxicity has been significant in some antiviral nucleoside analogs. For example, clinical trials for the use of the nucleoside analog have been made Fialuridine (FIAU) for the treatment of chronic hepatitis B of the recent exposed to liver failure in connection with the medicinal product, that led to death in some patients. Consequently, there is always There is still a need for safer drug dosage regimens for treatment of hepatitis B infections and hepatitis (Mutchnick, M.G., et al., Antiviral Research, 1994, 24, 245-257).

Out WO-A-95/22975 is the use of 1-deoxynojirimycin (DNJ) and its derivatives for the treatment of respiratory syncytial virus infected mammals known. The main difference between the cited prior art and the present application lies in the feature that W, X, Y and Z are independent from the group consisting of butanoyl, aroyl and trifluoroalkanoyl selected whereas in the cited prior art the corresponding ones are Designation means hydrogen or acetate.

The EP-A-0350012 relates to N-substituted-1-deoxynojirimycin derivatives Comprehensive antiviral compositions involving the formation of giant cells should effectively inhibit, and their use in therapy and Prophylaxis of AIDS. The N-arylalkyl compounds differ with respect to the present application, that W, X, Y and Z are hydrogen.

EP-A-0449026 describes novel deoxynojirimycin derivatives, a process for their preparation and their use in medicaments. The main difference between the known compounds and the compound of the present invention resides in the feature that the N-substituted group is selected from the group consisting of straight chain alkyl having a chain length of C ₇ to C ₂₀ , branched chain alkyl having a chain length of C ₃ to C ₂₀ in the main chain, alkoxyalkyl, arylalkyl and cycloalkylalkyl.

Out EP-A-0367748 discloses novel antiviral compounds which are known for Preparation of a medicament for administration to a host with the virus infected mammals useful should be. However, as can be seen, W, X, Y and Z are outside the corresponding claimed in the present invention Designations.

Although it appears that WO-A-95/19172 discloses the use of compounds for the treatment of He As regards B-virus infections, it will be seen that in the compounds of this invention the N-alkyl group is shorter. However, there is no suggestion or provision in this document for a basis for predicting that the alkyl chain known in the art should be extended.

The US-A-5 030 638 describes a method for antiviral potentiation, according to which N-alkyl derivatives of 1,5-dideoxy-1,5-imino-D-glucitol amplifying the antiviral activity serve. The disclosed N-alkyl derivatives have a relation to the Compounds of the present application different nonyl or Tetradecylalkyl chain.

immunomodulators and immune stimulants

Immunomodulators / immunostimulants such as α-interferon and other cytokines are involved in the treatment of HBV infection promising results have been used. Unfortunately, they were the reaction levels less than desired. The interferon treatment is currently being treated by the FDA approved by hepatitis B. Further, affecting the immune system Drug candidates are currently under investigation. These include Thymus peptides for use in the treatment of chronic Hepatitis B (CHB), isoprinosine, steroids, Schiff bases Salicylaldehyde derivatives such as tucaresol, levamisole and the like (Gish, R.G., et al., Exp. Opin Invest Invest Drugs, 1995, 4 (2), 95-115; Coates, J.A.V. et al., Exp. Opin. Ther. Patents, 1995, 5 (8), 747-765).

SUMMARY THE INVENTION

As mentioned above, is the combination of the N-substituted-imino-D-glucitol compounds disclosed herein and the derivatives thereof alone or in combination with others Anti-hepatitis virus compounds to the knowledge of the inventors The present invention has neither been proposed nor disclosed. The use of two or more antiviral agents for delivery an improved therapy for the treatment of hepatitis B virus infections is due to morbidity and mortality the disease desirable. Combination therapies are also desirable as they increase patient toxicity because they allow the doctor to lower doses to administer one or more of the medicines that the Patient receives. Combination therapy can also help the development of drug resistance in patients (Wiltink, E.H.H., Pharmaceutish Weekblads Scientific Edition, 1992, 14, (4A), 268-274). The result of an improved efficacy configuration combined with a relative lack of toxicity and development of resistance would be one provide greatly improved drug treatment profile.

It is surprisingly The inventors have discovered that the use of N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds the treatment of hepatitis virus infections is effective. Farther led the use of these compounds in combination with antiviral Nucleoside or nucleotide compounds or combinations thereof and / or immunomodulators / immunostimulants to an unexpected one Measures greater effectiveness of the compounds against the hepatitis virus compared to the combined Antiviral activity expected from the individual components alone. Whether this on different mechanisms of action of the various drug classes used or other biological phenomena is due is present not clear.

worin R aus der Gruppe bestehend aus geradkettigem Alkyl mit einer Kettenlänge von C₇ bis C₂₀, verzweigtkettigem Alkyl mit einer Kettenlänge von C₃ bis C₂₀ in der Hauptkette, Alkoxyalkyl, Arylalkyl und Cycloalkylalkyl ausgewählt ist, und worin W, X, Y und Z jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Alkanoyl, Aroyl und Trifluoralkanoyl ausgewählt sind.Accordingly, in a first aspect, the present invention provides the use of an antiviral composition for the manufacture of a medicament for the treatment of hepatitis virus infection in a mammal comprising administering an antiviral hepatitis virus effective amount of at least one N-substituted-1,5 Dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof:

wherein R is selected from the group consisting of straight-chain alkyl having a chain length of C ₇ to C ₂₀ , branched chain alkyl having a chain length of C ₃ to C ₂₀ in the main chain, alkoxyalkyl, arylalkyl and cycloalkylalkyl is selected, and wherein W, X, Y and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl and trifluoroalkanoyl.

In a second embodiment the present invention provides the use of an antiviral Composition for the manufacture of a medicament for treatment a hepatitis virus infection in a mammal, comprising Comprising administering an antiviral composition to this mammal an antivirally effective amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof such as above.

In a third embodiment the present invention provides the use of an antiviral Composition for the manufacture of a medicament for treatment a hepatitis virus infection in a mammal, comprising Administering an antiviral composition to the mammal, in consisting essentially of an antiviral effective amount at least an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt as above.

In a fourth embodiment the present invention provides the use of an antiviral Composition for the manufacture of a medicament for treatment a hepatitis virus infection in a mammal, essentially consisting of the administration of an antivirally effective amount at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt as above of it to the mammal.

In a fifth embodiment the present invention provides the use of an antiviral Composition for the manufacture of a medicament for treatment a hepatitis virus infection in a mammal, essentially consisting of the administration of an antivirally effective amount an antiviral compound consisting essentially of at least an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof such as above to the mammal.

In a sixth embodiment The present invention provides the use of an antiviral composition for the manufacture of a medicament for the treatment of hepatitis virus infection in a mammal ready, consisting essentially of the administration of a first Amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof to the mammal and a second amount of an antiviral compound substantially exclusively the administration of any antiviral agent Nucleoside, a nucleotide, an immunomodulator or an immune stimulant, wherein the first and second amounts of the compounds together a anti-hepatitis virus effective amount of these compounds.

In a further embodiment the invention provides the use of an antiviral composition for the manufacture of a medicament for the treatment of hepatitis virus infection ready in a mammal, comprising administration of about 0.1 mg / kg / day to about 100 mg / kg / day of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof and from about 0.1 mg / person / day to about 500 mg / person / day one out the group consisting of antiviral nucleoside compounds, antiviral Nucleotide compounds selected Compound and a mixture thereof to the mammal.

In a further embodiment The present invention provides the use of an antiviral composition for the manufacture of a medicament for the treatment of hepatitis virus infection in a human patient, including administration from about 0.1 mg / kg / day to about 100 mg / kg / day of one of the group consisting of N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol or a pharmaceutically acceptable salt thereof, N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate or a pharmaceutically acceptable salt thereof, selected N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of formula I and mixtures thereof and of about 0.1 mg / person / day to about 500 mg / person / day of (-) - 2'-deoxy-3'-thiocytidine-5'-triphosphate to the human patient.

In a further embodiment The present invention provides the use of an antiviral composition for the manufacture of a medicament for the treatment of hepatitis virus infection in a mammal including the administration of an antivirally effective amount at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof as above to the mammal, essentially exclusively administration of an antiviral composition comprising Nucleoside, a nucleotide, an immunomodulator or an immune stimulant.

In a further embodiment The present invention provides the use of an antiviral composition for the manufacture of a medicament for the treatment of hepatitis virus infection in a mammal including the administration of an antivirally effective amount at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof as above, essentially exclusively the administration of others antiviral compounds except those of the formula I.

In a further embodiment The present invention provides a pharmaceutical composition ready comprising at least one antivirally effective amount N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof as above and a pharmaceutically acceptable carrier, excipient or a pharmaceutical acceptable diluent.

In a further embodiment The present invention provides a pharmaceutical composition prepared essentially consisting of an antiviral effective Amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof such as above and a pharmaceutically acceptable carrier, excipient or diluent.

In a further embodiment the present invention provides the use of a pharmaceutical A composition comprising an antivirally effective amount at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof as above, essentially free of a nucleoside, nucleotide, immunomodulator or immunostimulant, and a pharmaceutically acceptable carrier pharmaceutically acceptable diluent or a pharmaceutically acceptable excipient.

In a further embodiment The present invention provides a pharmaceutical composition ready comprising at least one antivirally effective amount N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof as above, in essentially free of other antiviral compounds except the Compounds of the formula I, and a pharmaceutically acceptable Carrier, a pharmaceutically acceptable diluent or a pharmaceutical acceptable excipient.

In yet another embodiment The present invention provides a composition comprising at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof as above and one from the group consisting of an antiviral nucleoside compound, an antiviral nucleotide compound, an immunomodulator, a Immunostimulant selected antiviral compound and mixtures thereof.

In an embodiment the present invention provides a pharmaceutical composition comprising a first amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof such as above, a second amount of one of the group consisting of a antiviral nucleoside compound, an antiviral nucleotide compound, an immunomodulator, an immune stimulant selected antiviral Compound and mixtures thereof and a pharmaceutically acceptable Carrier, a pharmaceutically acceptable diluent or a pharmaceutical acceptable excipient, wherein the first and second amounts of the Compounds together an antivirally effective amount of the compounds include.

In a further embodiment The present invention provides a pharmaceutical composition to treat a hepatitis B virus infection in a mammal, comprising from about 0.1 mg to about 100 mg of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof such as above, from about 0.1 mg to about 500 mg of one of the group compound selected from an antiviral nucleoside compound, an antiviral nucleotide compound and mixtures thereof and a pharmaceutically acceptable carrier pharmaceutically acceptable diluent or a pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a pharmaceutical composition for treating hepatitis B virus infection in a human patient, comprising from about 0.1 mg to about 100 mg of one of N- (n-nonyl). 1,5-dideoxy-1,5-imino-D-glucitol or a pharmaceutically acceptable salt thereof, N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate or a pharmaceutically acceptable Salt thereof, selected N-substituted-1,5-di desoxy-1,5-imino-D-glucitol compound of formula I or mixtures thereof, from about 0.1 mg to about 500 mg of (-) - 2'-deoxy-3'-thiocytidine-5'-triphosphate and a pharmaceutically acceptable carrier, or a pharmaceutically acceptable diluent or excipient.

In yet another embodiment The present invention provides a salt comprising a N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I as above and one from the group consisting of a nucleoside compound selected with an acidic moiety and a nucleotide.

In a further embodiment The present invention provides a method comprising reacting of N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol and (-) 2-deoxy-3'-thiocytidine-5'-triphosphate salt-forming Conditions and a salt produced thereby ready.

Of the Further scope of the applicability of the present invention will from the detailed description and provided below Drawings visible. However, it should be understood that the following detailed description and examples while they preferred embodiments indicate the invention, only for the purpose of illustration be specified, thus various changes and modifications within the spirit and scope of the invention to those skilled in the art of this detailed description.

SUMMARY THE DRAWINGS

The above and other objects, features and advantages of the present invention The invention will be better understood from the following detailed Description in conjunction with the accompanying, for illustrative purposes only and not for limitation of the present invention, which is as follows are:

1 shows the anti-hepatitis B virus activity of (-) - 2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC) alone and in combination with N-nonyl-DNJ in vitro.

2 Figure 10 shows the plasma concentration of N-nonyl-DNJ compared to the dose of N-nonyl-DNJ in samples taken during the dose in each experimental animal in Example 5. Laboratory animals are indicated with single letters and a low level of "background statistical noise" is at the dose level was added so that overlapping values were to be distinguished.

3 shows the slope of log (IPDNA + 10) of "week versus dose". A specific letter has been used for each experimental animal. The custom connection line applies to a four-parameter logistic model. The parameters of the fitted connection curve and their approximate standard errors are shown in the plot.

DETAILED DESCRIPTION OF THE INVENTION

The The following detailed description is provided to those skilled in the art to give an aid to the application of the invention. Nevertheless, this should be detailed description not inadmissible as a limitation of Be designed invention, if modifications and variations the embodiments herein be discussed, which can be made by the professional, without the mind and scope of the present inventive discovery.

The Contents of each mentioned patent specification and others mentioned herein References including the references mentioned in these primary references are herein incorporated by reference in their entirety.

in the Within the scope of the present invention, it has been found that the use of N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds is effective when used alone to treat hepatitis virus infections be used. It was added found that the combinations of N-substituted-1,5-dideoxy-1,5-imino-glucitol compounds with anti-hepatitis virus nucleosides or nucleotides and / or immunomodulators / immunostimulants also for this purpose are effective. There is some evidence that certain Combinations could inhibit hepatitis virus replication more than expected from the combined effect of the individual compounds would have been.

The present invention thus provides pharmaceutical compositions and their use in the manufacture of a medicament for the treatment of hepatitis virus infections, especially hepatitis B viral infections in humans, other mammals and cells using N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or either in combination with an antiviral nucleoside, an antiviral nucleotide, mixtures thereof, and / or an immunomodulating or immunostimulating agent. The N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds have basic nitrogen atoms and can be used in the form of a pharmaceutically acceptable salt. Nucleosides and nucleotides useful in the present invention are substituted purine or pyrimidine heterocycles which are further substituted with R ¹ in formulas II-VI at position 9 in the case of the purines or with R ¹ at position 1 in the case of the pyrimidines can. The immunomodulatory and immunostimulating agents useful in the present invention include those which are effective in stimulating the immune response in the control or elimination of viruses or other infectious agents. Non-limiting examples of such immunomodulating and immunostimulating agents include cytokines, peptide agonists, steroids, and classical drugs such as levamisole. The drug combinations of this invention may be for a cell or for cells, or for a human or other mammalian patient, either in separate pharmaceutically acceptable, concurrently or sequentially administered formulations, as formulations containing more than one therapeutic agent or as a selection of individual agents or multi-drug formulations. However they are administered, these drug combinations provide an anti-hepatitis virus effective amount of ingredients.

As As used herein, the term "anti-hepatitis virus effective amount" means one in the treatment hepatitis virus infection effective amount of N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound alone or a combined amount of (1) an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound either with an antiviral nucleoside, an antiviral nucleotide, a mixture of an antiviral nucleoside and an antiviral Nucleotide or an immunomodulating / immunostimulating agent (or mixtures thereof) or (2) a combined amount of one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound with an antiviral nucleoside, an antiviral nucleotide or a mixture thereof and an immunomodulating / immunostimulating Agent (or mixtures thereof). The antiviral efficacy of the aforementioned Compositions can be a variety of different, with virus replication and the virus assembly associated phenomena include. These can be used for Example, the blockage of hepatitis viral DNA synthesis, the Blocking viral transcription, blocking the assembly the virions blocking the release or release of the Virions from infected cells, blocking or alteration the function of viral proteins, including the function of the viral Coat protein / e and / or the formation of immature or otherwise non-functional Virions include. The overall effect is an inhibition of the viral Replication and infection of other cells and thus an inhibition the progression of infection in the patient.

N-substituted-1,5-dideoxy-1,5-imino-D-glucose compounds

worin R aus geradkettigem Alkyl mit einer Kettenlänge von C₇ bis C₂₀, insbesondere bevorzugt von C₈ bis C₂₀, insbesondere bevorzugt von C₈ bis C₁₆, insbesondere bevorzugt von C₈ bis C₁₂, sogar noch mehr bevorzugt von C₈ bis C₁₀ und am meisten bevorzugt C₉, verzweigtkettigem Alkyl mit einer Kettenlänge von C₃ bis C₂₀ in der Hauptkette, vorzugsweise C₃ bis C₁₆, insbesondere bevorzugt C₃ bis C₁₄, insbesondere bevorzugt C₄ bis C₁₂, insbesondere bevorzugt C₆ bis C₁₂ und sogar noch mehr bevorzugt C₈ bis C₁₀, Alkoxyalkyl, Arylalkyl und Cycloalkylalkyl ausgewählt ist. W, X, Y und Z sind unabhängig voneinander aus Wasserstoff, Alkanoyl, Aroyl und Trifluoralkanoyl ausgewählt.The N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds useful in the present invention are represented by structure I below

wherein R is straight chain alkyl having a chain length of C ₇ to C ₂₀ , more preferably from C ₈ to C ₂₀ , particularly preferably from C ₈ to C ₁₆ , particularly preferably from C ₈ to C ₁₂ , even more preferably from C ₈ to C ₁₀ and most preferably C ₉ , branched chain alkyl having a chain length of C ₃ to C ₂₀ in the main chain, preferably C ₃ to C ₁₆ , more preferably C ₃ to C ₁₄ , especially preferably C ₄ to C ₁₂ , most preferably C ₆ to C _12, and even more preferably C ₈ to C ₁₀ , alkoxyalkyl, arylalkyl and cycloalkylalkyl. W, X, Y and Z are independently selected from hydrogen, alkanoyl, aroyl and trifluoroalkanoyl.

Of the Expression "in the Main chain " the longest related or adjacent chain of carbon atoms starting at the attachment point a branched alkyl group to the nitrogen atom in the compounds the formula I.

The terms "alkoxy" and "alkyloxy" include linear or branched, oxygen-containing radicals each having alkyl moieties of one to about ten carbon atoms. In the present invention useful alkoxyalkyl groups ( "alkyl" - or "oxa" derivatives) can be C ₃ to C _20, preferably C ₄ to C _18, more preferably C ₅ to C _16, more preferably C ₆ to C _12, and even more more preferably C ₈ to C ₁₂ wherein 1 to 5 non-terminal carbon atoms, more preferably 1 to 3 non-terminal carbon atoms, may be replaced by oxygen.

Of the Term "aryl" alone or in combination with another remainder, one means one, two or three rings containing carbocyclic aromatic system, wherein the rings in appended Be connected or fused. The term "aryl" includes aromatic Radicals such as phenyl, naphthyl, tetrahydronaphthyl, indyl and biphenyl.

Of the The term "arylalkyl" embraces aryl-substituted ones Alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, Phenylethyl and diphenylethyl.

Of the The term "cycloalkyl" includes saturated carbocyclic Radicals having from 3 to about 12 carbon atoms. Especially preferred Cycloalkyl radicals are "lower cycloalkyl" radicals having 3 to about 8 carbon atoms. Examples of such radicals include cyclopropyl, Cyclobutyl, cyclopentyl and cyclohexyl. "Cycloalkylalkyl" means one with a cycloalkyl group substituted alkyl group.

The term "acyl" refers to a radical provided by the removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. "Alkanoyl" means branched and straight-chain alkanecarbonyl having a chain length of C ₁ to C ₂₀ , preferably C ₁ to C ₁₀ , particularly preferably C ₁ to C ₅ ; "Aroyl" means arylcarbonyl and "trifluoroalkanoyl" means alkanoyl containing 3-fluoro substituents. Examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and succinic, glycolic, glycolic, lactic, malic, tartaric, citric, ascorbic, glucuronic -, maleic, fumaric, pyruvic, almond, pantothene, β-hydroxybutyric, galactar and galacturonic acid formed residues.

If he in conjunction with another remainder when referring to the useful in the present invention Imino sugar is used, the term "alkyl" means an unbranched or branched chain of hydrocarbon radicals having 1 to 20 Carbon atoms, preferably of 1 to about 16 carbon atoms, especially preferably having from about 2 to about 12 carbon atoms, especially preferred having from about 3 to about 10 carbon atoms.

Of the The term "alkenyl" includes radicals having "cis" and "trans" orientations or alternatively "E" and "Z" orientations. The term "alkynyl" includes linear or branched radicals having at least one carbon-carbon triple bond from 2 to about 20 carbon atoms, or preferably 2 to about 12 carbon atoms. Particularly preferred alkynyl radicals are "lower alkynyl" radicals having 2 to about 6 carbon atoms. Examples of alkynyl radicals include Propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butenyl and 1-pentynyl.

The term "cycloalkylalkyl" includes alkyl radicals substituted with a cycloalkyl radical. Preferred cycloalkylalkyl radicals are C ₄ to C ₂₀ , in particular preferred cycloalkylalkyl radicals are C ₈ to C ₁₄ . "Lower cycloalkylalkyl" which includes lower alkyl radicals substituted with a lower cycloalkyl radical is defined above. Examples of such radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The The present invention includes any tautomeric forms of the compounds of formula I. The present invention also includes compounds of formula I having one or more asymmetric carbons. It is known to the person skilled in the art that these iminosugars according to the invention with asymmetric carbons in diastereomeric, racemic or optically active forms. All these forms will be considered as falling within the scope of this invention. In particular, the present invention includes enantiomers, diastereomers, racemic mixtures or other mixtures thereof.

Representative N-substituted-imino-D-glucitol compounds useful in the present invention are; without being limited thereto; the following:
N- (n-heptyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-octyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-undecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-dodecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-tridecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-pentadecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-hexadecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-heptadecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-octadecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-nonadecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-eicosyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (n-heptyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-octyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-decyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-undecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-dodecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-tridecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-pentadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-hexadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-heptadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-octadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-nonadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (n-eicosyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (2-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (4-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (5-methylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (3-propylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (1-Pentylpentylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (1-Butylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (7-methyloctyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (8-methylnonyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (9-methyldecyl) -1,5-dideoxy-1,5-imino-D-glucitol;
N- (10-methylundecyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (6-cyclohexylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (4-cyclohexylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (2-cyclohexylethyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (1-cyclohexylmethyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (1-phenylmethyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (3-phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (3- (4-methyl) phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (6-phenylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (2-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (4-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (5-methylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (3-propylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (1-Pentylpentylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (1-Butylbutyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (7-methyloctyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (8-methylnonyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (9-methyldecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (10-methylundecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (6-cyclohexylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (4-cyclohexylbutyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (2-cyclohexylethyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (1-cyclohexylmethyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (1-phenylmethyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (3-phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (3- (4-methyl) phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (6-phenylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (7-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (7-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat,
N- (7-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucittetraacetat,
N- (3-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (9-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (7-oxa-n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol,
N- (3-oxa-n-nonyl) -1,5-dideoxy-1,5-imino-D-glucittetraacetat,
N- (3-oxa-n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol and
N- (7,10,13-trioxa-n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol.

preferred Compounds are N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol and N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat.

The useful in the present invention N-substituted-imino-D-glucitol compounds, including the Prodrug, can be prepared by methods known in the art. For example discloses Example 13 of the U.S. Patent 5,144,037 discloses a process for the preparation of N-nonyl-DNJ. In column 4, line 62, U.S. Patent 4,806,650 discloses the preparation of various Alkoxy compounds, i. Alkoxy-substituted alkyl chains. U.S. Patent 4,260,622 discloses the preparation of numerous compounds. additional, in the preparation of N-substituted-imino-D-glucitol compounds and Prodrugs relevant documents include the US patents 4,182,767, 4,260,622, 4,611,058, 4,639,436 and 5,003,072, 5,411 970 and 5,115,519; International PCT Publication WO 95/19172 and Tan et al., 1991, Journal of Biological Chemistry 266, 22, 14504-14510 and the references cited herein. Method for introducing Oxygen in alkyl side chains are described in Tan et al., 1994, Glycobiology 4 (2), 141-149 and van den Broek et al., 1994, Recl. Trav. Chim. Pays-Bas 113, 107-116 discloses the preparation of ether oxygen-containing DNJ compounds.

When non-limiting, illustrative manufacturing process are shown below in Examples 1 and 2.

at In the treatment of hepatitis virus infections one can see the present N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in combination in the form of inorganic or organic acids use originating salts. These salts include without limitation limited to be the following: acetate, adipate, alginate, citrate, aspartate, Benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, Digluconate, cyclopentane propionate, dodecylsulfate, ethanesulfonate, Glucoheptanoate, glycerophosphate, hemisulphate, heptanoate, hexanoate, Fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, Lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, Oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, Pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.

The basic, nitrogen-containing groups can be reacted with agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromides and iodides, Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long-chain halides such as decyl, lauryl, myristyl and steryl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and others quaternized. Water or oil soluble or dispersible Products are thereby obtained as desired. The salts are through Combination of the basic compounds with the desired Acid formed.

nucleotides and nucleosides

In useful in the present invention Nucleosides and nucleotides are compounds of purine (II) - or Pyrimidine (III) basic compounds or analogs such as the compounds IV or V.

The numbering of positions for purines and pyrimidines is shown in structures II and III. R ¹ may be selected from hydroxyalkyl, hydroxyalkenyl, carboxyalkyl, carboxyalkenyl, thioalkyl, alkylthioalkyl, alkoxyalkyl, alkoxyalkenyl, heterocyclo, heterocycloalkyl, hydroxyalkylalkoxyalkyl, alkoxyalkylalkoxyalkyl and cycloalkylalkyl. The purine compounds may be further substituted at positions 1, 2, 3, 6, 7 or 8 of the purine heterocycles and the pyrimidine compounds at positions 2, 3, 4, 5 or 6 of the pyrimidine heterocycles. Such substituents may be selected from hydroxy, alkoxy, halogen, thiol, amino, carboxyl, monosubstituted amino, disubstituted amino and alkyl.

The following definitions are applicable only to the structures of Formulas II, III, IV, V and VI of the invention. When used in reference to purines and pyrimidines useful in this invention in combination with another group, the term "alkyl" means a straight or branched chain hydrocarbon group of 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. When used in conjunction with another group, the term "alkenyl" means straight or branched chain carbon groups having 1 or more double bonds of 2 to 8 carbon atoms, preferably 1 to 4 carbon atoms. When used solely with reference to purines and pyrimides useful in the present invention, the term "alkyl" means a straight chain or branched chain alkyl radical containing from 6 to 14 carbon atoms, preferably from 7 to 12 carbon atoms, and most preferably from 8 to 11 carbon atoms. The term "aryl", alone or in combination with a radical, means a phenyl, naphthyl or indenyl ring, optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, hydroxy or nitro. "Alkanoyl" means branched or straight-chain alkanecarbonyl having a chain length of C ₁ to C ₂₀ , preferably C ₂ to C ₁₄ , more preferably C ₄ to C ₁₀ , "aroyl" means arylcarbonyl and "trifluoroalkanoyl" means three fluoro-substituent-containing alkyl , "Halogen" means fluorine, chlorine, bromine or iodine. "Thiol" means hydrogen-substituted sulfur (-SH). "Amino" means nitrogen having two hydrogen atoms, "monosubstituted amino" and "disubstituted amino" mean independently amino groups further substituted with one or more arylalkyl groups. "Hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, "hydroxyalkenyl" means an alkenyl group substituted with one or more hydroxyl groups, "thioalkyl" means an alkyl substituted with one or more thiol (SH) groups, "alkoxyalkyl" means alkyl substituted with one or more alkyl ether groups, "alkoxyalkenyl" means an alkylene group-substituted alkenyl group, "hydroxyalkylalkoxyalkyl" means an alkoxyalkyl group substituted with a hydroxyalkyl group, "alkoxyalkylalkoxyalkyl" means an alkoxyalkyl group substituted with an alkoxyalkyl group, "cycloalkylalkyl" means one having Cycloalkyl group substituted alkyl group. The term "heterocycle" alone or in combination means a saturated or partially unsaturated, 5- or 6-membered ring containing multiple oxygen, nitrogen and / or sulfur heteroatoms. The heterocycle may be further substituted with 1 to 4 substituents which may independently be hydroxy, hydroxyalkyl, thiol, alkoxy, azido, nitro, halogen, amino, monosubstituted amino or disubstituted amino. Heterocycloalkyl means an alkyl group in which one or more hydrogen atoms are replaced by a substituted or unsubstituted heterocyclic ring.

Also included are the tautomers of the substituents on the compounds of the invention. Non-limiting examples of tautomers are ketone / enol automers, imino / amino tautomers, N-substituted imino / N-substituted amino tautomers, thiol / thiacarbonyl tautomers and ring chain tautomers such as the five- and six-membered oxygen, nitrogen, Sulfur or oxygen and sulfur-containing heterocycles, which also contain substituents in α-position with respect to the heteroatoms. Also in the present invention are specifically enantiomers and diastereomers as well as racemic and iso includes mixtures of the compounds discussed herein.

Representative nucleoside and nucleotide compounds also useful in the present invention include, but are not limited to, the following:
(+) - cis-5-fluoro-1- [2-hydroxymethyl) - [1,3-oxathiolan-5-yl] cytosine,
(-) - 2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC),
(-) - cis-5-fluoro-1- [2- (hydroxymethyl) - [1,3-oxathiolan-5-yl] cytosine (FTC),
(-) - 2 ', 3'-dideoxy-3'-thiacytidine [(-) - SddC],
1- (2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) -5-iodocytosine (FIAC),
1- (2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) -5-iodocytosine triphosphate (FIACTP),
1- (2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) -5-methyluracil (FMAU),
1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide,
2 ', 3'-Dideoxy-3'-fluoro-5-methyl-deoxycytidine (FddMeCyt),
2 ', 3'-Dideoxy-3'-chloro-5-methyl-deoxycytidine (ClddMeCyt),
2 ', 3'-dideoxy-3'-amino-5-methyl-deoxycytidine (AddMeCyt),
2 ', 3'-Dideoxy-3'-fluoro-5-methyl-cytidine (FddMeCyt),
2 ', 3'-dideoxy-3'-chloro-5-methyl-cytidine (ClddMeCyt),
2 ', 3'-dideoxy-3'-amino-5-methyl-cytidine (AddMeCyt),
2 ', 3'-dideoxy-3'-fluorothymidine (FddThd),
2 ', 3'-dideoxy-3'-beta-L-5-fluorocytidine (beta-L-FddC),
2 ', 3'-dideoxy-beta-L-5-thiacytidine,
2 ', 3'-dideoxy-beta-L-5-cytidine (beta-L-ddC),
9- (1,3-dihydroxy-2-propoxymethyl) guanine,
2'-deoxy-3'-thia-5-fluorocytosine,
3'-amino-5-methyl-deoxycytidine (AddMeCyt),
2-amino-1,9 - [(2-hydroxymethyl-1- (hydroxymethyl) ethoxy] methyl] -6H -purin-6-one (gancyclovir),
2- [2- (2-amino-9H-purin-9y) ethyl] -1,3-propanedi diacetate (famciclovir),
2-amino-1,9-dihydro-9 - [(2-hydroxyethoxy) methyl] 6H-purin-6-one (acyclovir),
9- (4-hydroxy-3-hydroxymethylbut-1-yl) guanine (penciclovir),
9- (4-hydroxy-3-hydroxymethylbut-1-yl) 6-deoxyguanine diacetate (famciclovir),
3'-azido-3'-deoxythymidine (AZT),
3'-chloro-5-methyl-deoxycytidine (ClddMeCyt),
9- (2-phosphonylmethoxyethyl) -2 ', 6'-diaminopurine-2', 3'-didesoxyribosid,
9- (2-phosphonylmethoxyethyl) adenine (PMEA),
Acyclovir triphosphate (ACVTP),
D-carbocyclic-2'-deoxyguanosine (CdG),
didesoxycytidine,
Dideoxycytosine (ddC),
Dideoxyguanine (ddG),
Didesoxyinosine (ddl),
E-5- (2-bromovinyl) -2'-deoxyuridine triphosphate,
Fluorarabinofuranosylioduracil,
1- (2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl) -5-iodouracil (FIAU), stavudine,
9-beta-D-arabinofuranosyl-9H-purine-6-amine monohydrate (Ara-A),
9-beta-D-arabinofuranosyl-9H-purine-6-amine 5'-monophosphate monohydrate (Ara-AMP),
2-deoxy-3'-thia-5-fluorocytidine,
2 ', 3'-dideoxyguanine and
2 ', 3'-dideoxyguanosine.

A preferred compound is (-) - 2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC).

synthetic Process for the preparation of nucleosides and nucleotides useful in accordance with the invention, as in Acta Biochim. Pole. 43, 25-36, 1996; Swed. Nucleosides Nucleotides 15, 361-378, 1996; Synthesis 12, 1465-1479, 1995, Carbohyd. Chem. 27, 242-276, 1995, Chem. Nucleosides Nucleotides 3, 421-535, 1994, Ann. Reports in Med. Chem, Academic Press and Exp. Opin. Invest. Drugs 4, 95-115, 1995 are well known to those skilled in the art.

The chemical reactions described in the references cited above are generally disclosed in terms of their broadest application for the preparation of the compounds of the invention. Occasionally, reactions may not be as described for each of the compounds within the scope of the instant disclosure be applicable. The compounds in which this occurs will be readily apparent to those skilled in the art. In all these cases, the reaction can be successfully carried out either by conventional modifications known to those skilled in the art, eg by appropriately protecting interfering groups, by switching to other conventional reagents, by routine modification of the reaction conditions and the like, or by other, otherwise disclosed or otherwise conventional ones Reactions to the preparation of the corresponding compounds of the invention be applicable. In all preparative methods, all starting materials are known or readily prepared from known starting materials.

While nucleoside analogues generally as they are present as antiviral agents used Need to become Nucleotides (nucleotide phosphates) sometimes to facilitate their Transports are converted by cell membranes to nucleosides. An example for one capable of penetrating cells, chemically altered Nucleotide is S-1-3-hydroxy-2-phosphonylmethoxypropylcytosine (HPMPC, Gilead Sciences).

Nucleoside according to the invention and nucleotide compounds in the form of acids can form salts. Examples include salts with alkali metals or alkaline earth metals such as Example sodium, potassium or magnesium or with organic bases or basic quaternary Ammonium salts.

immunomodulators and immune stimulants

A size Number of in the inventive method usable immunomodulators and immunostimulants is currently available. A List of these compounds is provided in Table 1 below.

TABLE 1

• AA-2G
• Adamantylamiddipeptid
• Adenosine deaminase, Enzon
• Adjuvant, Alliance
• Adjuvant, Ribi
• Adjuvant, Vaxcel
• Adjuvax
• Agelasphin-11
• AIDS therapy, Chiron
• Algalglucan, SRI
• Algammulin, Anutech
• Anginlyc
• anti Cellular Factors, Yeda
• Anticort
• Antigastrin-17 Immunogen, Ap
• Antigen release system, Vac
• Antigen formulation, IDBC
• AntiGnRH immunogen, Aphton
• Antiherpin
• Arbidol
• Aviron
• Azarol
• Bay-q-8939
• Bay-r-1005
• BCH-1393
• Betafectin
• Biostim
• BL-001
• BL-009
• Broncostat
• Cantastim
• CDRI-84-246
• cefodizime
• Chemokine Inhibitors, ICOS
• CMV peptides, City of Hope
• CN-5888
• Cytokine releasing agent, St
• DHEAS, paradigm
• DISC TA-HSV
• J07B
• I01A
• I01Z
• Ditiocarb sodium
• ECA-10-142
• ELS 1
• Endotoxin, Novartis
• FCE-20696
• FCE-24089
• FCE-24578
• FLT-3 ligand, Immunex
• FR-900483
• FR-900494
• FR-901235
• FTS-Zn
• G proteins, Cadus
• Gludapcin
• Glutaurin
• glycophosphopeptical
• GM 2
• GM-53
• GMDP
• Growth factor vaccine, EntreM
• H-BIG, NABI
• H-CIG, NABI
• HAB-439
• Helicobacter pylori vaccine
• Herpes-specific immune factor
• HIV Therapy, United Biomed
• HyperGAM + CF
• ImmuMax
• Immune BCG
• Immunotherapy, Connective
• Immomodulator, Evans
• Immunomodulators, Novacell
• IMREG-1
• IMREG-2
• Indomun
• Inosinpranobex
• Interferon, Dong-A (Alpha2)
• Interferon, Genentech (gamma)
• Interferon, Novartis (Alpha)
• Interleukin-12, Genetics Ins.
• Interleukin-15, Immunex
• Interleukin 16, Research Cor
• ISCAR-1
• J005X
• L-644,257
• Licomarasminsäure
• LipoTher
• LK-409
• LK-410
• LP-2307
• LT (r1926)
• LW-50020
• MAF, Shionogi
• MDP derivatives, Merck
• Metenkephalin, TNI
• Methylfurylbutyrolactone
• MIMP
• mirimostim
• mixed bacterial vaccines, Tem
• MM-1
• Moniliastat
• MPLA, Ribi
• MS-705
• murabutide
• Murabutid, Vacsyn
• Muramyl dipeptide derivatives
• Muramyl peptide derivatives
• Myelopid
• N-563
• NACOS-6
• NH-765
• NISV, Proteus
• NPT 16416
• NT-002
• PA-485
• PEFA 814
• Peptides, scios
• Peptidoglycan, Pliva
• Perthon, Advanced Plant
• PGM derivatives, Pliva
• Pharmaprojects No. 1099
• Pharmaprojects No. 1426
• Pharmaprojects No. 1549
• Pharmaprojects No. 1585
• Pharmaprojects No. 1607
• Pharmaprojects No. 1710
• Pharmaprojects No. 1779
• Pharmaprojects No. 2002
• Pharmaprojects No. 2060
• Pharmaprojects No. 2795
• Pharmaprojects No. 3088
• Pharmaprojects No. 3111
• Pharmaprojects # 3345
• Pharmaprojects No. 3467
• Pharmaprojects No. 3668
• Pharmaprojects No. 3998
• Pharmaprojects No. 3999
• Pharmaprojects No. 4089
• Pharmaprojects No. 4188
• Pharmaprojects No. 4451
• Pharmaprojects No. 4500
• Pharmaprojects No. 4689
• Pharmaprojects No. 4833
• Pharmaprojects No. 494
• Pharmaprojects No. 5217
• Pharmaprojects No. 530
• pidotimod
• Pimelautid
• pinafide
• PMD-589
• Podophyllotoxin, Conpharm
• POL-509
• poly-ICLC
• Poly-ICLC, Yamasa Shoyu
• Poly A-Poly U
• Polysaccharide A
• Protein A, Berlox Bioscience
• PS34WO
• Pseudomonas, monoclonal antibodies, Teijin
• Psomaglobin
• PTL 78419
• Pyrexol
• Pyriferon
• Retrogen
• Retropep
• RG-003
• Rhinostat
• Rifamaxil
• RM-06
• Rollin
• romurtide
• RU-40555
• RU-41821
• Rubella antibodies Resco
• 27609 S
• SB-73
• SDZ-280-636
• SDZ-MRL-953
• SK & F-107647
• SL04
• SL05
• SM-4333
• Solutein
• SRI 62-834
• SRL-172
• ST-570
• ST-789
• Staphage lysate
• Stimulon
• Suppressin
• T-150R1
• T-LCEF
• Tabilautid
• Temurtid
• Theradigm HBV
• Theradigm HPV
• Theradigm-HSV
• THF, Pharm. & Upjohn
• THF, Yeda
• thymalfasin
• Thymic hormone fractions
• Thymocartin
• Thymolymphotropin
• thymopentin
• Thymopentin analogues
• Thymopentin, Peptech
• Thymosin fraction 5, alpha
• thymostimulin
• thymotrinan
• TMD-232
• TO-115
• Transfer factor, Viragen
• Tuftsin, Selavo
• ubenimex
• Ulsastat
• ANGG-
• CD-4 +
• collag +
• COLSF +
• COM +
• DA-A +
• GUEST-
• GF-TH +
• GP-120
• IF +
• IF A +
• IF-A-2 +
• IF B +
• IF G +
• IF G-1B +
• II-2 +
• II-12 +
• II-15 +
• IM +
• LHRH +
• LIPCOR +
• LYM-B +
• LYM-NK +
• LYM-T +
• OPI +
• PEP +
• PHG-MA +
• RNA-SYN
• SY-CW
• TH-A-1 +
• TH-5 +
• TNF +
• U.N.

dosages

The useful in the invention N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds can be used in an amount in the range of about 0.1 mg / kg / day to about 100 mg / kg / day, in particular preferably from about 1 mg / kg / day to about 75 mg / kg / day, most preferably from about 5 mg / kg / day to about 50 mg / kg / day become.

The antiviral nucleoside or nucleotide compound or mixtures thereof can People in a range of about 0.1 mg / person / day to about 500 mg / person / day, preferably from about 10 mg / person / day to about 300 mg / kg / day, more preferably from about 25 mg / person / day to about 200 mg / person / day, even more preferably about 50 mg / person / day to about 150 mg / person / day, and most preferably in the range of about 1 mg / person / day to about 50 mg / person / day.

Immunomodulators and immunostimulants useful in accordance with the present invention may be administered in smaller amounts than known in the art. For example, thymosin alpha-1 and thymosin fraction 5 are typically administered to humans for the treatment of hepatitis B infections in an amount of 900 μg / ^m2 twice a week (Hepatology, 1988, 8, 1270, Hepatology, 1989, 10, 575, Hepatology, 1991, 14, 409; Gastroenterology, 1995, 108, A1127). In the methods and compositions of the invention, this dose may range from about 10 μg / ^m2 twice a week to about 750 μg / ^m2 twice a week, more preferably from about 100 μg / ^m2 twice a week to about 600 μg / m2 ² per week twice a week, most preferably from about 200 μg / ^m2 twice a week to about 400 μg / ^m2 twice a week. Interferon alpha is typically administered to humans for the treatment of hepatitis C infections in an amount of about 1 x 10 ⁶ units / person three times per week to about 10 x 10 ⁶ units / person three times per week (Simon et al., 1997, Hepatology 25, 445-448). In the invention In accordance with methods and compositions, this dose may range from about 0.1 x 10 ⁶ units / person three times a week to about 7.5 x 10 ⁶ units / person three times a week, more preferably from about 0.5 x 10 ⁶ to about 5 × 10 ⁶ units / person three times a week, most preferably from about 1 × 10 ⁶ units / person three times a week to about 3 × 10 ⁶ units / person three times a week.

by virtue of the amplified antiviral efficacy of these immunomodulators and immune stimulants against the hepatitis virus in the presence of the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds of the invention can reduced levels of other immunomodulators / immunostimulants the methods and compositions disclosed herein be used. These reduced quantities can be obtained through routine monitoring of the hepatitis virus in patients over the course of therapy become. This can be done, for example, by monitoring the hepatitis virus DNA in the patient serum by slot blot, dot blot or PCR techniques or by measuring hepatitis surface or other antigens such as antigen E in serum. Method for this in Hoofnagle et al., 1997, New. Engl. Journ. Med. 336, 5, 347-356 and F.B. Hollinger in Fields Virology, 3rd edition, Vol. 2, 1996, Bernard N. Fields et al., Ed., Chapter 86, "Hepatitis B Virus," pp. 2738-2807, Lippincott-Raven, Philadelphia, PA and the references cited therein.

The Patients can in a similar way Way during Combination therapy using N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds and the antiviral nucleoside and / or nucleotide agents for detection the for be monitored at the lowest effective dose.

The Dosages described above can a patient in a single dose or proportionate multiple Dosages are administered. In the latter case, the Dose unit compositions contain such pro rata amounts, that this results in the daily dose. By multiple doses The daily can also be daily Total dose increased This should be done by the prescribing person required become.

pharmaceutical compositions

The Compounds of the invention can be formulated as pharmaceutical compositions. Such Formulations can orally, parenterally, by inhalation spray, rectally, intradermally, transdermally or administered topically in unit dose formulations, which, if desired, conventional non-toxic carriers, Adjuvants and excipients included. Topical administration The use of transdermal administration may be like transdermal Plaster or with iontophoresis devices. The term parenteral, as used herein includes subcutaneous, intravenous, intramuscular or intrasternal injection or infusion procedure. The drug formulation is z. In Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975, and Liberman, H.A. and Lachman, L., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

injectable Preparations of, for example, sterile, injectable, aqueous or oily Suspensions can using dispersing or wetting agents known to those skilled in the art and suspending agents. The sterile injectable Preparation can also be a sterile injectable solution or Suspension in a non-toxic, for parenteral use acceptable dilution or Solvent, for example in a solution present in 1,3-butanediol. Among the acceptable and suitable Auxiliaries and solvents are water, wrestler solution and isotonic saline. additionally become sterile, non-volatile oils conventional as a solution or suspension media used. For this purpose, any colorless, non-volatile oil finally synthetic Mono- and diglycerides are used. In addition, fatty acids such as oleic acid may be used in the formulation of injection solutions useful be. Dimethylacetamide, surface-active Means including ionic and nonionic detergents and polyethylene glycol can be used. Mixtures of solvents and wetting agents, as discussed above are also useful.

suppositories for rectal administration of the compounds discussed herein may be Mix the drug with a suitable non-irritating excipient as cocoa butter or polyethylene glycol are produced at normal temperatures, but are liquid at the rectal temperature and therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of the invention will usually be combined with one or more adjuvants suitable for the given route of administration ned. When administered orally, the compounds may be treated with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and or polyvinyl alcohol and then tableted or filled into capsules for convenient administration. Such capsules or tablets may contain a controlled release formulation as may be provided in a dispersion of the active ingredient in hydroxypropyl methylcellulose. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents such as sodium citrate or magnesium or calcium carbonate or bicarbonate. Tablets and pills may additionally be made with a small intestine soluble coating.

For therapeutic Purposes can the formulations for parenteral administration in the form of aqueous or non-aqueous, isotonic, sterile Injek tion solutions or suspensions. These solutions or suspensions can be made from sterile powders or granules containing a or more of the above for use in oral formulations Mentioned administration Carrier- or diluents contain. The connections can in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, Sodium chloride and / or different buffers are dissolved. Other adjuvants and methods of administration will be apparent to those skilled in the art Well and widely known in the pharmaceutical field.

Liquid dosage forms for oral administration pharmaceutically acceptable, inert, usually lege artis used thinner such as water-containing emulsions, solutions, suspensions, syrups and elixirs. Such compositions may also Adjuvants, such as wetting agents, emulsifiers and suspending agents and sweet, flavored and fragrances.

The Amount of active ingredient with the carrier materials be combined to produce a single dosage form can, hangs on the patient and the particular mode of administration.

Certain the pharmaceutical of the invention Compounds that comply with with the inventive method can be administered as a pro-drug for further compounds of the invention serve. Pro-drugs are drugs that are administered in vivo or in in vitro chemically converted to the (n) active derivative or derivatives can be. Pro-drugs are administered essentially the same way like the other pharmaceutical according to the invention Links. Non-limiting examples are the esters of the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds according to the invention.

links the combinations according to the invention, e.g. N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol and various Nucleosides or nucleotides can acids or bases. As such, they can for salt formation are used together. Nucleosides are purines or pyrimidine compounds lacking a phosphate ester. links the formulas II, III, IV, V or VI described herein which are not phosphate esters, but a carboxylic acid moiety contain a salt with an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the invention. Nucleotides are purine or pyrimidine compounds, the mono-, di- or triphosphate esters. These phosphate esters contain free -OH groups which are acidic and which are inorganic or organic Bases can form salts. The salt formation with organic bases depends on the pKa of the acid and the base off. The N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds disclosed herein are basic and form pharmaceutically acceptable salts. In the present Case can useful Salts are not only formed with pharmaceutically acceptable acids, but also with biologically active acids, such as the nucleosides and nucleotides disclosed herein. These salts can on for The salt production can be made conventionally, the the expert is known. For example, the free base of a N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound having a nucleotide analog of formulas II, III, IV, V or VI are treated for salt formation. This can be as a separate chemical reaction or as part of the formulation process carried out become. The limiting reagent in the salt-forming reaction is either the acid or the base, as understood by one skilled in the art to obtain a suitable biological Selects result. The formulation can be as desired Mixtures of various salts, acids or free bases. For example, the phosphoric acid form of (-) - 2'-deoxy-3'-thiocytidine-5'-triphosphate a salt with the basic Form of N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol or N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate. This type of salt can then be used for the patient in a pharmaceutically acceptable formulation as pure single salt or in the form of a mixture can be provided.

In some cases, the salts may also be used as an aid in isolation, purification or trening tion of the compounds of the invention are used.

treatment regimen

The Treatment scheme of a person suffering from a hepatitis virus infection Patients with the compounds of the invention and / or compositions will be in accordance with a variety selected from factors including Age, weight, sex, diet and medical condition of the patient, severity of the infection, Route of administration, pharmacological considerations such as activity, efficacy, Pharmacokinetics and toxicological profiles of special administered compounds and whether a system for drug release is used.

Administration of the drug combinations disclosed herein should generally continue for a period of several weeks to several months or years until virus titres reach acceptable levels, indicating that the infection has been controlled or eradicated. As noted above, patients undergoing treatment may routinely by measuring the hepatitis virus DNA in the patient's serum by slot blot, dot-blot or PCR techniques or by measuring hepatitis antigens such as hepatitis B surfaces Antigen (HBsAg) and the hepatitis E antigen (HBeAg) in the serum to determine the efficacy of the therapy. For example, in chronic hepatitis B, remissions may be characterized by the disappearance of viral hepatitis B DNA, ie, a reduction to undetectable levels, as measured by hybridization capable of detecting levels ≥10 ⁵ genomes / per ml serum and HBeAG from serum Tests, despite continued presence of HBsAG. These serological events are followed by an improvement in biochemical and histological disease characteristics. The endpoint of successful treatment in most antiviral therapy attempts is the disappearance of HBeAg and viral DNA from the serum. In patients in whom the E antigen disappears, remission is usually maintained and this leads to an inactive status as an HBsAg carrier. Many patients eventually become HBsAg-negative (see Hoofnagle et al., 1977, New Engl. Jour., Med. 336 (5), 347-356 for a review).

continued Allow analyzes of the results obtained by these methods a modification in the treatment plan during therapy, so that optimal amounts of each component of the combination are administered can and with that as well the duration of treatment can be determined. Thus, the treatment plan / the Dosing scheme in reasonable Way over the course of therapy will be modified to allow the lowest levels the respective antiviral compounds used in combination, which together show satisfactory anti-hepatitis virus activity and thus the administration of such antiviral compounds in combination only as long as it continues to successful Treatment of the infection is required.

The following, non-limiting Examples serve to illustrate various embodiments of the present invention.

example 1

Preparation of 1,5- (butylimino) -1,5-dideoxy-D-glucitol

A solution of 1,5-dideoxy-1,5-imino-D-glucitol (5.14 g, 0.0315 M), butyraldehyde (3.35 mL, 0.0380 M) and palladium black (1 g) in 200 ml of methanol was hydrogenated (60 psi, 29 ° C / 21 h). After filtering the resulting mixture, the filtrate was concentrated in vacuo to an oil. The title compound was crystallized from acetone and recrystallized from methanol / acetone, mp. 132 ° C. The structure assignment was supported by NMR, infrared spectrum and elemental analysis.
Analysis calculated for C ₁₀ H ₂ NO ₄ : C, 54.78, H, 9.65, N, 6.39.
Found: C 54.46, N 9.33, N 6.46.

Example 2

Preparation of 1,5- (butylimino) -1,5-dideoxy-D-glucitol tetraacetate

Acetic anhydride (1.08 g, 0.0106 M) was added to the title compound of Example 1 (0.50 g, 0.0023 M) in 5 mL of pyridine and stirred for 17 days at room temperature. The product was evaporated under nitrogen gas. The resulting title compound was purified by silica gel chromatography. The structure assignment was confirmed by NMR, infrared spectrum and elemental analysis.
Analysis calculated for C ₁₈ H ₂₉ NO _8: C 55.80, H 7.54, N 3.62.
Found: C 55.42, H 7.50, N 3.72.

Example 3

Anti-hepatitis B virus activity of various N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in vitro

• ¹Chronisch HBV-ausschüttende 2.2.15 Zellen (etwa 500 000 pro Cavität) wurden in Gegenwart der angegebenen Verbindung während 3 Tagen inkubiert.
• ²Nach 3 Tagen in Kultur in Abwesenheit oder Gegenwart einer Testverbindung wurden die Zellen durch Trypsin-Behandlung entfernt, mit Trypanblau inkubiert und durch mikroskopische Inaugenscheinnahme auf Farbausschluss untersucht. Die Werte sind Prozentangaben von Trypanblau ausschließenden Zellen, bezogen auf die Gesamtzahl der untersuchten Zellen (Trypanblau-Ausschluss wird als gleichbedeutend mit lebensfähig angesehen).
• ³Nach 3 Tagen der Inkubation in Abwesenheit oder Gegenwart einer Testverbindung wurden die ausgeschütteten Virionen aus dem Kulturmedium mit einem für das preS1-Antigen spezifischen monoklonalen Antikörper immunpräzipitiert (Meisel et al., 1995, Intervirology 37, 330–339; Lu et al., 1995, Virology 213, 660–665). Im Immunpräzipitat vorhandene virale DNA wurde durch densitometrische Quantifi zierung der aus einer Polymerase-Kettenreaktion erhaltenen DNA-Fragmente mit der korrekten Größe nachgewiesen. Die Menge der aus der Kontrolle amplifizierten DNA (Zellen ohne Testverbindung) wird als 100% gesetzt.
• ⁴NBDNJ: N-(n-Butyl)-1,5-Didesoxy-1,5-imino-D-glucit, N-Butyl-DNJ
• ⁵Obwohl Trypanblau-Färbung auf Lebensfähigkeit nicht durchgeführt wurde, erschienen die Zellen bei der groben mikroskopischen Untersuchung unauffällig (gesund).
• S.D. = Standardabweichung

Efficacy against hepatitis B virus and cell viability of a number of different N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds are employed using an in vitro assay assessed by chronic hepatitis virus-releasing HepG2.2.15 cells. The method used was essentially as described by Block et al., 1994, Proc. Natl. Acad. Sci. USA 91, 2235-2239. The results are shown in Tables 2 and 3. TABLE 2 Effect of N-substituted 1,5-dideoxy-1,5-imino-D-glucitol compounds on hepatitis B virus secretion and viability of HepG2.2.15 cells

• ¹ Chronic HBV-releasing 2.2.15 cells (approximately 500,000 per well) were incubated in the presence of the indicated compound for 3 days.
• ² After 3 days in culture in the absence or presence of a test compound, the cells were removed by trypsin treatment, were incubated with trypan blue and examined by microscopic inspection on dye exclusion. The values are percentages of trypan blue-excluding cells based on the total number of cells examined (trypan blue exclusion is considered to be equivalent to viable).
• ³ After 3 days of incubation in the absence or presence of a test compound, the distributed virions Intervirology 37, 330-339 were prepared from the culture medium with an antibody specific for the preS1 antigen monoclonal antibody immunoprecipitated (Meisel et al, 1995,;.. Lu et al, 1995, Virology 213, 660-665). Viral DNA present in the immunoprecipitate was detected by densitometric quantification of the DNA fragments of the correct size obtained from a polymerase chain reaction. The amount of DNA amplified from the control (cells without test compound) is set as 100%.
• ⁴ NBDNJ: N- (n-butyl) -1,5-dideoxy-1,5-imino-D-glucitol, N-butyl-DNJ
• ⁵ Although trypan blue staining for viability was not performed, the cells appeared unremarkable (healthy) on gross microscopic examination.
• SD = standard deviation

Links:

• 1) N- (3-phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucitol
• 2) N- (n-butyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate
• 3) N- (2-ethylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol

TABLE 3 Effect of N-substituted 1,5-dideoxy-1,5-imino-D-glucitol compounds on hepatitis B virus secretion and viability of HepG2.2.15 cells

• ¹ in μg per ml and based on PCR duplicate determinations
• ² in μg per ml; MTT: 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide. The assay performed by colorimetry based on MTT is a measure of the viability of cells (Heo et al., 1990, Cancer Research 50, 3681-3690).
• ³ not determined
• * lowest tested concentration
• ** it was at the highest used concentration (200 μg / ml) no inhibition seen.

Links:

• 1) N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol
• 2) N- (n-butyl) -1,5-dideoxy-1,5-imino-D-glucitol, 3,4-diacetate.

Example 4

Anti-hepatitis B virus activity of (-) - 2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC) alone and in combination with N-nonyl-DNJ

The Anti-hepatitis B virus action of (-) - 2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC) alone and in combination with N-nonyl-DNJ was prepared according to Korba, 1996, Antiviral Research 29 (1), 49-51, using the "Combostat" method (Comstat Program, Combostat Corp., Duluth, MN). The Combostat method includes serial dilution from IC-90 of each connection. The IC-90 of N-nonyl-DNJ was used as intermediate 4 and 10 μg / ml determined (T. Block and G. Jacob, unpublished observations). The approved IC-90 for 3TC in HepG 2.2.15 (2.2.15) cells is 300 nM to 500 nM (Doong et al., 1991, Proc. Natl. Acad. Sci. USA 88, 8495-8499).

2.2.15 cells, as described in Sells et al., 1987, Proc. Natl. Acad. Sci. USA 84, 1005-1009 were maintained in RPMI 1640 medium (Gibco BRL, # 31800-022) supplemented with 10% fetal calf serum albumin, 200 μg / ml G418 (Gibco BRL 066-1811). The cells were resuspended at 80% confluency in 25 cm ² tissue culture flasks. Five days later, three culture bottles each received either no compound, serial dilutions of 3TC alone, or serial dilutions of 3TC plus N-nonyl-DNJ. On days 2, 4 and 6, after addition of the compound (with culture medium exchange on those days), the amount of hepatitis B virus DNA was determined by PCR analysis from polyethylene glycol sedimented particles. Thus, in these experiments viral envelopes were not distinguished from nucleocapsids. The PCR amplified products were separated by agarose gel electrophoresis (1.5% agarose) and the 538 nucleotide fragment quantitated by scanning the band (HP Jet Imager). The amount of HBV recovered from untreated cells was assumed to be 100%. The results for the 6-day time are in 1 represented as average values of at least 3 individual culture bottles and the standard deviation was never greater than 20% with an average error of 12%.

For each of the The series tested at three time points was the combination of 3TC plus N-nonyl-DNJ the HBV release significantly more effective than any of the compounds alone. Conclusions based on the PCR analysis alone made it difficult to assign exact IC-50 values. The extreme sensitivity and the Sensitive operation of the PCR may be considered, for example, for inability more than 90% inhibition with 3TC, even at 300 nM. Each experiment included controls to make sure that the PCR was performed in the range of DNA concentrations in which the reaction results proportional to the amount of DNA in the sample. The resolution is about 3 times, i. 3-fold differences in DNA concentrations can be detected. The inability consistently proving less than 3-fold differences, probably explains 3TC alone failed to reach more than 90% inhibition. This suggests that in PCR a very high level of inhibition must be achieved in order to prove it. Consequently, the trend is for three separate Times clear: the combined effect of 3TC plus N-nonyl-DNJ is bigger than each compound alone or the additive individual effect each Connection. These results suggest that the IC-50 for 3TC of about 60 nM shifted to about 0.48 mM when 0.016 μg / ml N-nonyl-DNJ are present.

Example 5

Anti-Hepatitis B virus effect of N-nonyl-DNJ alone in a woodchuck model

to Evaluation of the efficacy of N-nonyl-DNJ in combination with 3TC (or other nucleoside or nucleotide analogues) against hepatitis B virus in a woodchuck animal model, first became a monotherapy attempt performed using N-nonyl-DNJ alone. This was necessary to determine if N-nonyl-DNJ has any anti-HBV activity Woodchuck has and, if N-Nonyl-DNJ a useful one Effect has a combination therapy based on the dose-response relationship to design this medicine alone.

Therefore were 5 groups each with 4 animals (all groups consisted of Animals of both sexes, except in the controls, there were two of each sex) for doses of 0, 12.5, 25, 50 and 100 mg / kg / day twice daily Oral intake divided. It was a laboratory-mounted one Wildlife. All animals were born as newborns with the woodchuck hepatitis virus (WHV) and positive for the WHV surface antigen in serological tests tested. Blood samples were taken one week before dosing (-1 week), immediately after dosing (0 weeks), weekly during dosing (1, 2, 3 and 4 weeks) and after completion of dosing (5, 6, 8 and 10 Weeks).

It There are two methods of measuring drug effectiveness: reduction HBV total DNA (measured by quantitative PCR) and reduction of HBV DNA Capsids with intact surface glycoproteins, which represents the active form of the virus (measured in an ELISA-like immunoprecipitation followed by quantitative PCR). Cell culture experiments with N-nonyl-DNJ showed little or no effect of this compound on total HBV DNA, but a significant effect on the immunoprecipitated DNA (IPDNA). Not surprising the IPDNA assay is quite variable; as a partial compensation for it performed four assays, the respective samples of all animals, but different sample approaches for the study weeks contained.

Around to summarize the results, N-nonyl-DNJ showed no effect on HBV total DNA measurements taken at all dose levels during the period Pre-dose intake proportion and during dose proportion of the study were essentially constant. On the other hand, there were IPDNA levels during the study period not constant. The low dose animals showed a tendency to increasing levels of IPDNA during the dose-giving period (0-4 weeks), while Animals with higher Doses tend to decrease levels of IPDNA over the same Period showed. Put a straight line through the weekly ones Reactions of each animal showed a clear difference in the slope of this line either due to the dosage or the plasma level of the drug. The plasma drug levels were also quite variable: animals with the lowest plasma levels in their dose group had lower plasma levels than animals with the highest Plasma levels from the next lower dosage group. There were no differences in any of the measurements between the reactions of male and female animals.

plasma levels

There was no clear pattern in the changes in plasma levels of N-nonyl-DNJ that could have been related to the week of dosing or the time of the previous dose. Since the Plas Mirrors were reasonably consistent in one animal during dosing, the mean plasma level of each animal was used for subsequent modeling. Plasma levels for each week of the dose-giving period were plotted over the dose for each animal (a small amount of "background statistical noise" was added to the dose levels to distinguish the points on top of each other) ( 2 ).

HBV DNA

The HBV total DNA levels were for Essentially each animal over the time constant (results not shown). There was a weak one Indication of a dose-response relationship with decreasing virus levels at increasing drug levels, except that three animals in the highest Dose had very high virus levels. It is not possible that Conclusion to draw that there is some relationship between N-nonyl-DNJ dose and total HBV DNA. It is possible that there are two populations of experimental animals, namely responders (like experimental animals r) and non-responders (like the experimental animals i, m and d), but it More data is needed to make a safe conclusion at this point to allow.

immunoprecipitated HBV DNA

It There were significant variations in the IPDNA assays, both between individual assay runs as well as within an assay run (results not shown). Nevertheless, it was possible while the weeks 0-4 to observe and design a slope that is generally at Animals with low doses increases and animals with high levels Doses decreases. This change in the slope was statistically significant (p <0.005).

Before a model was assigned to the results became a log transformation applied because 1) the variance in IPDNA with increasing IPDNA values increases; the log transformation yields values with a nearly constant Variance, and 2) it is expected that drug effects as constant factor appears at the IPDNA level. As with IPDNA Zero values, a small value (about half of the smallest value above zero) before the log transformation all values added.

Two approaches were used to make the changes in the slope with respect to "week with N-nonyl-DNJ dose" for modeling to use: a linear model and a non-linear model. Both approaches assume that the (linear) extent of the log (IPDNA) measurement over the Dosing period, the "correct" measurement for playback the drug effect on the virus. Both approaches are phased, and the first phase has both approaches in common. First is a regression model in the form of a simple line suitable, the weeks 0-4 to the forecast for Log (IPDNA + 10) separated for every animal used in combination of runs. In the second Phase is the reaction variable that matches the first phase Pitch.

at The linear approach is a model with a slope over the Week in response to where a run is considered as a block the dose has a significant effect (almost all of this Effect is based on slope versus dose) and the relevant Error in testing the dose effect the variation between equally treated Animals (after adjusting the runs as blocks) is appropriate. This is similar to Using the calibration results within each run, to get first the results of each run to the usual virus DNA concentration adapt; the difference here is that the results of the Woodchucks are more for run-through adaptation than just calibration results be used.

The non-linear approach adapts a four-parameter logistic model with the slope over the week as the response and the dose as the predictor. Again, a run is considered a block, but because there is no run every week, it is not possible to fully render the block map in the non-linear approach. Nevertheless, the non-linear model gives an EC-50 value of 7.88 mg / kg / 2 x daily dose. The observed average maximum slope was 2.71 plus log (IPDNA μg / ml / week) or an increase of approximately 150% / week, the average minimum slope observed for N-nonyl-DNJ was 0.31 minus log (IPDNA μg / ml / Week or about a decrease of about 25% / week The slopes, the fitted model, the model estimated parameters and the approximate standard error for these parameters are in 3 shown. The results show an approximate effective monotherapy dose of N-nonyl-DNJ in woodchucks of about 16 mg / kg / day. In both woodchucks and humans, the effective dose of both the N-alkyl DNJ and the nucleoside or nucleotide thus administered as an antiviral agent can be given in two equal daily sub-doses (ie, twice daily).

2 and 3 show letters to designate animals. Table 4 shows two of the codes used for the animals, sex and dose.

TABLE 4 Animal Coding, Gender and Dose

Example 6

Antiviral studies for the activity test of N-nonyl-DNJ in combination with 3TC in the woodchuck model of the Hepatitis B virus infection

The combined activity of N-nonyl-DNJ and the nucleoside analogue 3TC can be synthesized using the Woodchuck model of hepatitis virus infection can be assessed. 28 woodchucks with persistent hepatitis virus infection (WHV) can be used. Groups of woodchucks are taken orally 3TC alone (once a day), with N-nonyl-DNJ alone (twice a day) or with a combination both drugs treated. The antiviral activity of the individual medicinal products and the combinations can by measuring WHV DNA in serum during treatment and by Comparison of treated groups to those treated with placebo Control groups are assessed.

28 woodchucks with established, persistent WHV infection can be used, all were experimentally infected with WHV during their first week of life. All can be positive WHsAg at baseline.

All in all can 8 experimental groups are used. Woodchucks can go up the basis of sex, body weight and age are each assigned to the groups. 3TC can be taken orally as aqueous Suspension of Epivir (Glaxo-Wellcome) tablets once a day be administered. N-nonyl-DNJ can also be found in aqueous Suspension distributed to two doses orally. Of the Treatment with the two drugs may be the administration of 4 to 5 ml of a semi-synthetic liquid woodchuck feed Follow to the full Ensure intake of medicines.

The experimental groups can be as follows:

The Woodchucks can anesthetized (50 mg / kg ketamine, 5 mg / kg cylazine), weighed and pre-treated the first treatment, in weekly Intervals during the 6 weeks Treatment phase and 1, 2 and 4 weeks after completion of treatment Blood samples are taken. Serum can be collected and aliquoted be split. An aliquot may be used to analyze the WHV DNA Dot blot hybridization and for the ELISA determination of WHsAg before treatment and at the end of treatment be used. A second aliquot may be in a sample archive remain. Additional serum aliquots may be used for drug analysis and for special WHV DNA analyzes are used.

Claims (26)

Use of an antiviral composition consisting essentially of an antivirally effective amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of formula 1 or a pharmaceutically acceptable salt thereof:

wherein R is selected from the group consisting of straight chain alkyl having a chain length of C ₇ to C ₂₀ , branched chain acyl having a chain length of C ₃ to C ₂₀ in the backbone, alkoxyalkyl, arylalkyl and cycloalkylalkyl, and wherein W, X, Y and Each Z is independently selected from the group consisting of hydrogen, alkanoyl, aroyl and trifluoroalkanoyl, for the manufacture of a medicament for the treatment of hepatitis viral infection in a mammal. Use according to claim 1, wherein R is a straight-chain alkyl having a chain length of C ₇ to C ₂₀ and W, X, Y and Z are each hydrogen. Use according to claim 2, wherein R is nonyl. Use according to claim 1, wherein R is straight-chain alkyl having a chain length of C ₇ to C ₂₀ and W, X, Y and Z are each alkanoyl. Use according to claim 4, wherein R is nonyl. Use according to claim 5, wherein the alkanoyl is butanoyl is. Use according to claim 1, wherein the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol is selected from the group consisting of N- (n-heptyl) -1,5-dideoxy-1,5-imino -D-glucitol, N- (n-octyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-nonyl) -1,5-dideoxy-1,5-imino-D glucitol, N- (n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-undecyl) -1,5-dideoxy-1,5-imino-D-glucitol , N- (n-dodecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-tridecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N - (n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-pentadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- ( n-hexadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-heptadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-) Octadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-nonadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-eicosyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-heptyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-octyl) -1 , 5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-decyl) -1,5 -dideoxy-1,5-imino-D-glucittetr abutyrate, N- (n-undecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-dodecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-tridecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-pentadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-hexadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n -Heptadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-octadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-nonadecyl ) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-eicosyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (2-ethylhexyl) - 1,5-dideoxy-1,5-imino-D-glucitol, N- (4-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (5-methylhexyl) -1, 5-dideoxy-1,5-imino-D-glucitol, N- (3-propylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (1-pentylpentylhexyl) -1,5- dideoxy-1,5-imino-D-glucitol, N- (1-butyl-butyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (7-methyloctyl) -1,5-dideoxy 1,5-imino-D-glucitol, N- (8-methylnonyl) -1,5-di desoxy-1,5-imino-D-glucitol, N- (9-methyldecyl) -1,5-dideoxy-1,5-imino-D-glucitol; N- (10-methylundecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (6-cyclohexylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (4-Cyclohexylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (2-cyclohexylethyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (1 Cyclohexylmethyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (1-phenylmethyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (3-phenylpropyl ) -1,5-dideoxy-1,5-imino-D-glucitol, N- (3- (4-methyl) phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- ( 6-phenylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (2-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (4-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (5-methylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (3-propylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1 Pentylpentylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-butylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (7-methyloctyl ) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (8-methylnonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (9-methyldecyl) - 1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (10-methylundecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (6-cyclohexylhexyl) -1, 5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (4-cyclohexylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (2-cyclohexylethyl) -1,5- dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-cyclohexylmethyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-phenylmethyl) -1,5-dideoxy- 1,5-imino-D-glucitol tetrabutyrate, N- (3-phenylpropyl) -1,5-dideoxy- 1,5-imino-D-glucitol tetrabutyrate, N- (3- (4-methyl) phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (6-phenylhexyl) -1,5 dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (7-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (7-oxa-n- decyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (7-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol tetraacetate, N- ( 3-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (9-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D glucitol, N- (7-oxa-n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (3-oxa-n-nonyl) -1,5-dideoxy-1 , 5-imino-D-glucitol tetraacetate, N- (3-oxa-n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol and N- (7,10,13-trioxa-n- tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol. Use according to claim 1, wherein the pharmaceutically acceptable salt from the group consisting of acetate, adipate, alginate, Citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, Camphorsulfonate, digluconate, cyclopentaneproprionate, dodecylsulfate, Ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, Hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, Maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, Palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, Propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate selected is. Use of an antiviral composition containing an antiviral effective amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof:

substantially exclusively the administration of any antiviral agent comprising a nucleoside, a nucleotide, an immunomodulator or an immunostimulant, wherein R is selected from the group consisting of straight-chain alkyl having a chain length of C ₇ to C ₂₀ , branched chain alkyl having a chain length of C ₃ to C _{20 is selected} in the main chain, alkoxyalkyl, arylalkyl and cycloalkylalkyl, and wherein W, X, Y and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl and trifluoroalkanoyl for the manufacture of a medicament for the treatment of hepatitis viral infection in a mammal. Use according to claim 9, wherein R is a straight-chain alkyl having a chain length of C ₇ to C ₂₀ and W, X, Y and Z are each hydrogen. Use according to claim 10, wherein R is nonyl. Use according to claim 9, wherein R is a straight-chain alkyl having a chain length of C ₇ to C ₂₀ and W, X, Y and Z are each alkanoyl. Use according to claim 12, wherein R is nonyl. Use according to claim 13, wherein the alkanoyl Butanoyl is. Use according to claim 9, wherein the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of N- (n-heptyl) -1,5-dideoxy-1,5 -imino-D-glucitol, N- (n-octyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-nonyl) -1,5-dideoxy-1,5-imino -D-glucitol, N- (n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-undecyl) -1,5-dideoxy-1,5-imino-D glucitol, N- (n-dodecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-tridecyl) -1,5-dideoxy-1,5-imino-D-glucitol , N- (n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-pentadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N - (n-hexadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-heptadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- ( n-octadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-nonadecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-) Eicosyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (n-heptyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-octyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-decyl) -1 , 5-dideoxy-1,5-imino-D glucitol tetrabutyrate, N- (n-undecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-dodecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate , N- (n-tridecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N - (n-pentadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-hexadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- ( n-heptadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-octadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n- Nonadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-eicosyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (2-ethylhexyl) 1,5-dideoxy-1,5-imino-D-glucitol, N- (4-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (5-methylhexyl) -1 , 5-dideoxy-1,5-imino-D-glucitol, N- (3-propylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (1-pentylpentylhexyl) -1,5 dideoxy-1,5-imino-D-glucitol, N- (1-butyl-butyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (7-methyloctyl) -1,5-dideoxy -1,5-imino-D-glucitol, N- (8-methylno nyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (9-methyldecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (10-methylundecyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (6-cyclohexylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (4-cyclohexylbutyl) -1 , 5-dideoxy-1,5-imino-D-glucitol, N- (2-cyclohexylethyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (1-cyclohexylmethyl) -1,5 dideoxy-1,5-imino-D-glucitol, N- (1-phenylmethyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (3-phenylpropyl) -1,5-dideoxy -1,5-imino-D-glucitol, N- (3- (4-methyl) phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (6-phenylhexyl) -1, 5-dideoxy-1,5-imino-D-glucitol, N- (2-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (4-ethylhexyl) -1,5- dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (5-methylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (3-propylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-pentylpentylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-Butylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (7-methyloctyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (8 -Methylnonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (9-methyldecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (10-methylundecyl ) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (6-cyclohexylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (4-cyclohexylbutyl) - 1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (2-cyclohexylethyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-cyclohexylmethyl) -1, 5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-phenylmethyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (3-phenylpropyl) -1,5- dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (3- (4-methyl) phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (6-phenylhexyl) -1 , 5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (7-oxa-n-decyl) - 1,5-dideoxy-1,5-imino-D-glucitol, N- (7-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (7-oxa -n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol tetraacetate, N- (3-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (9-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol, N- (7-oxa-n-nonyl) -1,5-dideoxy-1,5- imino-D-glucitol, N- (3-oxa-n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetraacetate, N- (3-oxa-n-nonyl) -1,5- dideoxy-1,5-imino-D-glucitol and N- (7,10,13-trioxa-n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol. Use according to claim 9, wherein the pharmaceutically acceptable salt from the group consisting of acetate, adipate, alginate, Citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, Camphorsulfonate, digluconate, cyclopentaneproprionate, dodecylsulfate, Ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, Hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, Lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, Oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, Pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate selected is. A pharmaceutical composition consisting essentially of an antivirally effective amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the formula I or a pharmaceutically acceptable salt thereof:

wherein R is selected from the group consisting of straight-chain alkyl having a chain length of C ₇ to C ₂₀ , branched chain alkyl having a chain length of C ₃ to C ₂₀ in the backbone, alkoxyalkyl, arylalkyl and cycloalkylalkyl, and wherein W, X, Y and Each Z is independently selected from the group consisting of butanoyl, aroyl and trifluoroalkanoyl, and a pharmaceutically acceptable carrier, excipient or diluent. A pharmaceutical composition according to claim 17, wherein R is a straight-chain alkyl having a chain length of C ₇ to C ₂₀ and W, X, Y and Z are each butanoyl. A pharmaceutical composition according to claim 18, wherein R is nonyl. The pharmaceutical composition of claim 17, wherein the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound is selected from the group consisting of N- (n-heptyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-octyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n -Nodecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-dodecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-tridecyl ) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-pentadecyl) - 1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-hexadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-heptadecyl) -1, 5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-octadecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-nonadecyl) -1,5- dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (n-eicosyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (2-ethylhexyl) -1,5-dideoxy- 1,5-imino-D-glucitol tetrabutyrate, N- (4-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (5-methylhexyl) -1,5-dideoxy-1, 5-imino- D-glucitol tetrabutyrate, N- (3-propylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-pentylpentylhexyl) -1,5-dideoxy-1,5-imino-D- glucitol tetrabutyrate, N- (1-butylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (7-methyloctyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (8-methylnonyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (9-methyldecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (10-Methylundecyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (6-cyclohexylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (4 Cyclohexylbutyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (2-cyclohexylethyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-cyclohexylmethyl ) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (1-phenylmethyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (3-phenylpropyl) - 1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (3- (4-methyl) phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucitol tetrabutyrate, N- (6- phenylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyr at, N- (7-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucitol tetraacetate and is selected. Pharmaceutical composition according to claim 17, wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, Bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, Dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, Heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, Picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate selected is. A pharmaceutical composition containing an antivirally effective amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of formula I or a pharmaceutically acceptable salt thereof.

substantially exclusively an antiviral agent comprising a nucleoside, a nucleotide, an immunomodulator or an immune stimulus, wherein R is selected from the group consisting of straight-chain alkyl having a chain length of C ₇ to C ₂₀ , branched chain alkyl having a chain length of C ₃ to C ₂₀ in the main chain, alkoxyalkyl, arylalkyl and cycloalkylalkyl wherein W, X, Y and Z are each independently selected from the group consisting of butanoyl, aroyl and trifluoroalkanoyl and a pharmaceutically acceptable carrier, diluent or excipient. A pharmaceutical composition according to claim 22, wherein R is a straight-chain alkyl having a chain length of C ₇ to C ₂₀ and W, X, Y and Z are each butanol. Pharmaceutical composition according to claim 23, wherein R is nonyl. A pharmaceutical composition according to claim 22, wherein the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound consisting of the group N- (n-heptyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-octyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-nonyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-decyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-undecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-dodecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-tridecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-tetradecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-pentadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-hexadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-heptadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-octadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-nonadecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (n-eicosyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (2-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (4-ethylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (5-methylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (3-propylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (1-Pentylpentylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (1-Butylbutyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (7-methyloctyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (8-methylnonyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (9-methyldecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (10-methylundecyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (6-cyclohexylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (4-cyclohexylbutyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (2-cyclohexylethyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (1-cyclohexylmethyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (1-phenylmethyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (3-phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (3- (4-methyl) phenylpropyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat, N- (6-phenylhexyl) -1,5-dideoxy-1,5-imino-D-glucittetrabutyrat and N- (7-oxa-n-decyl) -1,5-dideoxy-1,5-imino-D-glucittetraacetat is selected. A pharmaceutical composition according to claim 22, wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, Bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, Dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, Heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, Picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoates selected is.